Ozone-induced airway hyperresponsiveness: role of superoxide anions, NEP, and BK receptors

1995 ◽  
Vol 78 (3) ◽  
pp. 1015-1022 ◽  
Author(s):  
H. Tsukagoshi ◽  
E. B. Haddad ◽  
J. Sun ◽  
P. J. Barnes ◽  
K. F. Chung
Keyword(s):  
Airway Hyperresponsiveness ◽  
Lavage Fluid ◽  
Airway Responsiveness ◽  
Ozone Exposure ◽  
Brown Norway ◽  
Superoxide Anions ◽  
Norway Rat

We investigated the role of reactive oxygen species in ozone-induced airway hyperresponsiveness (AHR) in Brown Norway rats. Airway responsiveness to inhaled acetylcholine (ACh) and bradykinin (BK) and inflammatory cell recruitment in bronchoalveolar lavage fluid (BALF) were measured in vivo. Neutral endopeptidase (NEP) activity assay and measurement of BK-receptor binding sites in Brown Norway rat lungs were carried out in vitro. Apocynin (5 mg/kg), an inhibitor of superoxide anion-generating NADPH oxidase, was administered perorally 30 min before a 3- or 6-h exposure to 3 ppm of ozone, and the animals were studied 18–24 h postexposure. Ozone induced increases in airway responsiveness to ACh and BK and in neutrophil counts in BALF. Apocynin inhibited the increase in airway responsiveness to BK but not to ACh without affecting the neutrophil counts in BALF. The antioxidants allopurinol and deferoxamine prevented ozone-induced AHR to both ACh and BK but did not reduce neutrophil counts. To further examine the mechanisms of ozone-induced AHR to BK, we measured NEP activity and the density of BK receptors in vitro after ozone exposure. Ozone exposure had no significant effect either on NEP activity or on the affinity and the number of BK receptors in lungs from rats treated with or without apocynin. We conclude that superoxide anions released from inflammatory cells in the airway may be involved in ozone-induced AHR. Inactivation of NEP or upregulation of BK receptors do not appear to be involved, but the possibility of localized changes cannot be excluded.

Allergen-induced airway hyperresponsiveness in Brown-Norway rat: role of parasympathetic mechanisms

1993 ◽  
Vol 75 (1) ◽  
pp. 279-284 ◽  
Author(s):  
W. Elwood ◽  
T. Sakamoto ◽  
P. J. Barnes ◽  
K. F. Chung
Keyword(s):  
Airway Hyperresponsiveness ◽  
Allergen Challenge ◽  
Electrical Field Stimulation ◽  
Airway Responsiveness ◽  
Brown Norway ◽  
Field Stimulation ◽  
Electrical Field ◽  
Norway Rat

Enhanced parasympathetic mechanisms may contribute to airway hyperresponsiveness. The present study examined whether the in vivo increase in airway responsiveness seen 18–24 h after either a single or chronic aerosolized allergen challenge protocol in actively sensitized Brown-Norway rats was due to altered parasympathetic mechanisms. The roles of central and reflex vagal mechanisms were studied by performing bilateral cervical vagotomy before measurement of airway responsiveness. Bilateral vagotomy failed to reduce the increase in airway responsiveness after either a single or chronic allergen challenge. The roles of increased neural release of acetylcholine (ACh) and increased end organ responsiveness were studied in vitro. The isometric responses of tracheal and bronchial strips to both electrical field stimulation and exogenously applied ACh from rats exposed both to single and chronic allergen challenges were compared with those from saline-exposed rats. The responses to electrical field stimulation and to exogenous ACh were not significantly enhanced 18–24 h after either protocol. We conclude that the airway hyperresponsiveness observed in this allergic rat model is not mediated through an enhancement of parasympathetic mechanisms.

Effect of ozone exposure in vivo on response of bronchial rings in vitro: role of intracellular Ca2+

1993 ◽  
Vol 75 (3) ◽  
pp. 1315-1322 ◽  
Author(s):  
L. M. Montano ◽  
G. L. Jones ◽  
P. M. O'Byrne ◽  
E. E. Daniel
Keyword(s):  
Airway Hyperresponsiveness ◽  
Cyclopiazonic Acid ◽  
Ozone Exposure ◽  
Organ Bath ◽  
Krebs Solution ◽  
Free Solution ◽  
Dry Air

In this study we investigated the role of intracellular Ca2+ in ozone- (O3) induced airway hyperresponsiveness. Acetylcholine-induced airway responses were measured before and after inhalation of O3 (3 ppm, 30 min) or dry air. In vitro experiments were performed with intact ring segments of third- to fifth-order bronchi. Bronchial responses to carbachol (CCh) were evaluated in Krebs solution (2.5 mM Ca2+) and in Ca(2+)-free [0.1 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA)] Krebs solution with or without indomethacin (IDM, 10(-5) M) and were expressed as percentage of the maximal KCl response (60 mM). Inhalation of O3, but not dry air, caused airway hyperresponsiveness to acetylcholine in vivo. Responses to 50% effective concentrations of CCh were similar in bronchial preparations from O3 and control animals (with or without IDM) in normal Krebs solution. In Ca(2+)-free solution, CCh induced a sustained (20-min) bronchial contraction. These contractions relaxed immediately when nifedipine or a high EGTA concentration was added to the organ bath. The sustained contraction was abolished when the tissues had been incubated with cyclopiazonic acid (10(-5) M), a novel inhibitor of the sarcoplasmic reticulum Ca2+ pump. After O3 exposure, responses of the bronchial smooth muscle (in Ca(2+)-free medium without IDM) were increased (P < 0.05) compared with controls during the first and second CCh stimulations. This O3-induced increase in response to CCh in Ca(2+)-free solution was abolished when the tissues were incubated with IDM.(ABSTRACT TRUNCATED AT 250 WORDS)

O3-induced airway hyperresponsiveness to noncholinergic system and other stimuli

1992 ◽  
Vol 73 (1) ◽  
pp. 354-361 ◽  
Author(s):  
M. G. Campos ◽  
P. Segura ◽  
M. H. Vargas ◽  
B. Vanda ◽  
H. Ponce-Monter ◽  
...  
Keyword(s):  
Substance P ◽  
Bronchoalveolar Lavage ◽  
Guinea Pigs ◽  
Airway Hyperresponsiveness ◽  
Airway Responsiveness ◽  
Insufflation Pressure

The effect of O3 exposure (3 ppm, 1 h) on the in vivo and in vitro airway responsiveness, as well as the changes in cell contents in bronchoalveolar lavage (BAL) fluid, were evaluated 16–18 h after O3 exposure in sensitized and nonsensitized male guinea pigs. The sensitization procedure was performed through repeated inhalation of ovalbumin for 3 wk. Increase in pulmonary insufflation pressure produced by the excitatory nonadrenergic noncholinergic (eNANC) system, histamine, and antigen were assessed in in vivo conditions, whereas airway responsiveness to histamine and substance P was evaluated in in vitro conditions by use of tracheal chains with or without epithelium and lung parenchymal strips. We found that O3 exposure 1) increased the neutrophil content in BAL fluids in both sensitized and nonsensitized guinea pigs, 2) caused hyperresponsiveness to eNANC stimulation in nonsensitized guinea pigs (although combination of sensitization and O3 exposure paradoxically abolished the hyperresponsiveness to eNANC stimulation), 3) increased the in vivo bronchoconstrictor responses to histamine and antigen, 4) caused hyperresponsiveness to substance P in nonsensitized tracheae with or without epithelium and in sensitized tracheae with epithelium, 5) did not modify the responsiveness to histamine in tracheae with or without epithelium (and in addition, epithelium removal caused hyperresponsiveness to histamine even in those tracheae exposed to O3), and 6) produced hyperresponsiveness to histamine in lung parenchymal strips either from sensitized or nonsensitized guinea pigs.

Inhibitory action of Wnt target gene osteopontin on mitochondrial cytochrome c release determines renal ischemic resistance

2010 ◽  
Vol 299 (1) ◽  
pp. F234-F242 ◽  
Author(s):  
Jose Luis Viñas ◽  
Anna Sola ◽  
Michaela Jung ◽  
Chrysoula Mastora ◽  
Eugenia Vinuesa ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Wnt Pathway ◽  
Brown Norway ◽  
Mitochondrial Cytochrome ◽  
Cytochrome C Release ◽  
Norway Rats ◽  
Mitochondrial Cytochrome C

Certain determinants of ischemic resistance in the Brown Norway rat strain have been proposed, but no studies to date have focused on the role of the Wnt pathway in the ischemic resistance mechanism. We performed a comparative genomic study in Brown Norway vs. Sprague-Dawley rats. Selective manipulations of the Wnt pathway in vivo and in vitro allowed us to study whether the action of the Wnt pathway on apoptosis through the regulation of osteopontin was critical to the maintenance of inherent ischemic resistance mechanisms. The results revealed a major gene upregulation of the Wnt family in Brown Norway rats after renal ischemia-reperfusion. Manipulation of the Wnt signaling cascade by selective antibodies increased mitochondrial cytochrome c release and caspase 3 activity. The antiapoptotic role of Wnt was mediated by osteopontin, a direct Wnt target gene. Osteopontin was reduced by Wnt antibody administration in vivo, and osteopontin gene silencing in vitro significantly increased mitochondrial cytochrome c release. The overexpression of Wnt pathway genes detected in Brown Norway rats is critical in the maintenance of their inherent ischemic resistance. Activation of the Wnt signaling cascade reduces mitochondrial cytochrome c release and caspase 3 activity through the action of osteopontin.

scholarly journals Drug Ligand-Induced Activation of Translocator Protein (TSPO) Stimulates Steroid Production by Aged Brown Norway Rat Leydig Cells

Endocrinology ◽  
2013 ◽  
Vol 154 (6) ◽  
pp. 2156-2165 ◽  
Author(s):  
J.-Y. Chung ◽  
H. Chen ◽  
A. Midzak ◽  
A. L. Burnett ◽  
V. Papadopoulos ◽  
...  
Keyword(s):  
Leydig Cells ◽  
Translocator Protein ◽  
Brown Norway ◽  
Aged Rats ◽  
Steroid Production ◽  
Norway Rat ◽  
Rate Determining Step ◽  
In Vitro Effects

Abstract Translocator protein (TSPO; 18 kDA) is a high-affinity cholesterol-binding protein that is integrally involved in cholesterol transfer from intracellular stores into mitochondria, the rate-determining step in steroid formation. Previous studies have shown that TSPO drug ligands are able to activate steroid production by MA-10 mouse Leydig tumor cells and by mitochondria isolated from steroidogenic cells. We hypothesized herein that the direct, pharmacological activation of TSPO might induce aged Leydig cells, which are characterized by reduced T production, to produce significantly higher levels of T both in vitro and in vivo. To test this, we first examined the in vitro effects of the TSPO selective and structurally distinct drug ligands N,N-dihexyl-2-(4-fluorophenyl)indole-3-acetamide (FGIN-1-27) and benzodiazepine 4′-chlorodiazepam (Ro5-4864) on steroidogenesis by Leydig cells isolated from aged (21-24 months old) and young adult (3-6 months old) Brown Norway rats. The ligands stimulated Leydig cell T production significantly, and equivalently, in cells of both ages, an effect that was significantly inhibited by the specific TSPO inhibitor 5-androsten-3,17,19-triol (19-Atriol). Additionally, we examined the in vivo effects of administering FGIN-1-27 to young and aged rats. In both cases, serum T levels increased significantly, consistent with the in vitro results. Indeed, serum T levels in aged rats administered FGIN-1-27 were equivalent to T levels in the serum of control young rats. Taken together, these results indicate that although there are reduced amounts of TSPO in aged Leydig cells, its direct activation is able to increase T production. We suggest that this approach might serve as a therapeutic means to increase steroid levels in vivo in cases of primary hypogonadism.

scholarly journals Tidal stretches do not modulate responsiveness of intact airways in vitro

2010 ◽  
Vol 109 (2) ◽  
pp. 295-304 ◽  
Author(s):  
Adam S. LaPrad ◽  
Thomas L. Szabo ◽  
Béla Suki ◽  
Kenneth R. Lutchen
Keyword(s):  
Smooth Muscle ◽  
Ultrasound Imaging ◽  
Airway Hyperresponsiveness ◽  
Breathing Pattern ◽  
Airway Responsiveness ◽  
Integrated System ◽  
Airway Constriction ◽  
Static Conditions

Studies on isolated tracheal airway smooth muscle (ASM) strips have shown that length/force fluctuations, similar to those likely occurring during breathing, will mitigate ASM contractility. These studies conjecture that, solely by reducing length oscillations on a healthy, intact airway, one can create airway hyperresponsiveness, but this has never been explicitly tested. The intact airway has additional complexities of geometry and structure that may impact its relevance to isolated ASM strips. We examined the role of transmural pressure (Ptm) fluctuations of physiological amplitudes on the responsiveness of an intact airway. We developed an integrated system utilizing ultrasound imaging to provide real-time measurements of luminal radius and wall thickness over the full length of an intact airway ( generation 10 and below) during Ptm oscillations. First, airway constriction dynamics to cumulative acetylcholine (ACh) doses (10−7 to 10−3 M) were measured during static and dynamic Ptm protocols. Regardless of the breathing pattern, the Ptm oscillation protocols were ineffective in reducing the net level of constriction for any ACh dose, compared with the static control ( P = 0.225–0.793). Next, Ptm oscillations of increasing peak-to-peak amplitude were applied subsequent to constricting intact airways under static conditions (5.0-cmH2O Ptm) with a moderate ACh dose (10−5 M). Peak-to-peak Ptm oscillations ≤5.0 cmH2O resulted in no statistically significant bronchodilatory response ( P = 0.429 and 0.490). Larger oscillations (10 cmH2O, peak to peak) produced modest dilation of 4.3% ( P = 0.009). The lack of modulation of airway responsiveness by Ptm oscillations in intact, healthy airways suggests that ASM level mechanisms alone may not be the sole determinant of airway responsiveness.

Adrenomedullin insufficiency increases allergen-induced airway hyperresponsiveness in mice

2007 ◽  
Vol 102 (6) ◽  
pp. 2361-2368 ◽  
Author(s):  
Hiroshi Yamamoto ◽  
Takahide Nagase ◽  
Takayuki Shindo ◽  
Shinji Teramoto ◽  
Tomoko Aoki-Nagase ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Airway Responsiveness ◽  
Mutant Mice ◽  
Wild Type ◽  
T Helper 1 ◽  
Littermate Control

Adrenomedullin (ADM), a newly identified vasodilating peptide, is reported to be expressed in lungs and have a bronchodilating effect. We hypothesized whether ADM could be involved in the pathogenesis of bronchial asthma. We examined the role of ADM in airway responsiveness using heterozygous ADM-deficient mice ( AM+/−) and their littermate control ( AM+/+). Here, we show that airway responsiveness is enhanced in ADM mutant mice after sensitization and challenge with ovalbumin (OVA). The immunoreactive ADM level in the lung tissue after methacholine challenge was significantly greater in the wild-type mice than that in the mutant. However, the impairment of ADM gene function did not affect immunoglobulins (OVA-specific IgE and IgG1), T helper 1 and 2 cytokines, and leukotrenes. Thus the conventional mechanism of allergen-induced airway responsiveness is not relevant to this model. Furthermore, morphometric analysis revealed that eosinophilia and airway hypersecretion were similarly found in both the OVA-treated ADM mutant mice and the OVA-treated wild-type mice. On the other hand, the area of the airway smooth muscle layer of the OVA-treated mutant mice was significantly greater than that of the OVA-treated wild-type mice. These results suggest that ADM gene disruption may be associated with airway smooth muscle hyperplasia as well as enhanced airway hyperresponsiveness. ADM mutant mice might provide novel insights to study the pathophysiological role of ADM in vivo.

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